Previous studies have demonstrated that immune activation secondary to microbial coinfections or vaccinations induces a transient burst of HIV viremia. Microbial pathogens or their products may also interact with HIV or its target cells and influence HIV replication in coinfected individuals. In order to investigate the effects of immune activation on the pathogenesis of HIV disease, we set up an in vitro model system. During physiological antigen presentation from professional antigen presenting cells (APC) to T cells, interactions between CD28 on T cells and B7 molecules on APC play a critical role in inducing efficient and appropriate stimulation of T cells. To mimic in vivo antigen presentation that occurs during microbial coinfections, CD4+ T cells are costimulated with both CD3 crosslinking and CD28/B7 interactions. Using this system, we have found that signaling through the two costimulatory molecules appears to have distinct effects on HIV infection. Costimulation with CD3 and B7-1 rendered the cells susceptible to, while costimulation with CD3 and B7-2 rendered the cells relatively resistant to HIV infection. Furthermore, through supernatant swapping experiments, we have found that this effect is due, at least in part, to soluble factors secreted by B7-2-stimulated cells. Previous studies have demonstrated that immune activation secondary to microbial coinfections or vaccinations induces a transient burst of HIV viremia. Microbial pathogens or their products may also interact with HIV or its target cells and influence HIV replication in coinfected individuals. In order to investigate the effects of immune activation on the pathogenesis of HIV disease, we set up an in vitro model system. During physiological antigen presentation from professional antigen presenting cells (APC) to T cells, interactions between CD28 on T cells and B7 molecules on APC play a critical role in inducing efficient and appropriate stimulation of T cells. To mimic in vivo antigen presentation that occurs during microbial coinfections, CD4+ T cells are costimulated with both CD3 crosslinking and CD28/B7 interactions. Using this system, we have found that signaling through the two costimulatory molecules appears to have distinct effects on HIV infection. Costimulation with CD3 and B7-1 rendered the cells susceptible to, while costimulation with CD3 and B7-2 rendered the cells relatively resistant to HIV infection. Furthermore, through supernatant swapping experiments, we have found that this effect is due, at least in part, to soluble factors secreted by B7-2-stimulated cells. and STRL33, and the CC chemokine gene RANTES. These studies suggest that co-infection with a wide array of microbial pathogens (for example, bacteria and HTLV-I) generally leads to a more favorable environment for T-tropic HIV-1 infection and a less favorable or sometimes unfavorable environment for M-tropic HIV-1 infection, thereby accelerating the transition from M- to T-tropic phenotype, which is indicative of disease progression in HIV infected individuals. Finally, we are investigating possible interactions between HIV and herpes simplex virus (HSV). Genital herpes may enhance the efficiency of sexual transmission of HIV, and HSV-encoded transactivators are known to upregulate expression from the HIV long terminal repeat. Recently, one of the HSV entry receptors was identified as a member of the TNF receptor family. We hypothesized that signaling through the HSV receptor may influence expression of and susceptibility to HIV by stimulating lymphocytes and/or macrophages, targets for both viruses. We have demonstrated that exposure of those cells to heat-inactivated HSV virions induces HIV expression.